人乳腺癌细胞(MCF-7)中溴代咔唑与雌激素受体和芳香烃受体的交叉作用
Cross-talk of Bromocarbazoles between Estrogen Receptor Pathway and Aryl Hydrocarbon Receptor Pathway in Human Breast Cancer Cells (MCF-7 Cells)
-
摘要: 卤代咔唑是一类与二噁英结构类似的杂环芳香烃化合物，在环境和生物体内均有检出。研究表明，溴代咔唑（bromocarbazoles，BCZs）是具有代表性的卤代咔唑，有较强的持久性和生物累积性，且在不同生物体内表现出类二噁英毒性以及内分泌干扰效应，对人类的健康有潜在风险。研究表明BCZs可以在不同细胞中分别激活芳香烃受体（aryl hydrocarbon receptor，AhR）和雌激素受体（estrogen receptor，ER）。乳腺癌的发生发展不仅与ER通路密切相关，也与AhR通路有关，但在乳腺癌细胞中BCZs对2种通路的相互作用机制尚不明确。因此，本研究以BCZs对ER和AhR通路的作用为目标，有助于我们借助不良结局途径（adverse outcome pathway，AOP），从分子层面了解BCZs对乳腺癌细胞毒理学作用机制。实验选取5种BCZs，以ER阳性的人乳腺癌细胞（MCF-7）为研究对象，探究BCZs在MCF-7细胞中对ER和AhR通路的激活作用，并筛选激活能力最强的BCZs，探究2个通路之间的相互作用。结果表明，1，3，6，8-四溴咔唑（1，3，6，8-tetrabromo-9H-carbazole，1368-BCZ）可以同时激活ER和AhR通路，上调ER通路靶基因三叶因子1（trefoil factor 1，tff1）和AhR通路靶基因细胞色素P450酶1A1（cytochrome P450 1A1，cyp1a1）和细胞色素P450酶1B1（cytochrome P450 1B1，cyp1b1）的表达水平；1368-BCZ对ER通路的激活部分依赖于ahr的介导，而干扰ER通路的激活作用后，AhR通路下游代表性目的基因的表达水平提高。因此，1368-BCZ是一种可以同时激活ER和AhR通路的BCZs，且被激活的ER和AhR通路之间存在相互作用。本实验补充了BCZs在ER阳性乳腺癌细胞中的可能作用机制，为新型污染物BCZs的毒性效应机制研究提供了数据支持。Abstract: Polyhalogenated carbazoles are heterocyclic aromatic hydrocarbon compounds with a similar structure to dioxins, which have been detected in environments and organisms. Among them, bromocarbazoles (BCZs) present strong persistence and bioaccumulation potential, and have shown dioxin-like toxicity and endocrine disrupting effects in different organisms, posing potential risks to human health. Studies have shown that BCZs can activate aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) in different types of cells. The ER and AhR pathway are closely related to the occurrence and development of breast cancer. However, the interactions between the ER and AhR pathways induced by BCZs in human breast cancer cells remained unclear. Therefore, the aim of this study is to shed light on the interaction of BCZs with the ER and AhR signaling pathways in breast cancer cells in order to provide a new perspective for clarifying the breast cancer-related adverse outcome pathways that BCZs may trigger. In this study, we selected 5 BCZs to explore the activation effects of BCZs on ER and AhR pathways in ER-positive human breast cancer cells MCF-7. Interactions between the AhR and ER signaling pathways were also studied for BCZs, which has the strongest receptor activation capabilities. The results showed that 1,3,6,8-tetrabromo-9H-carbazole (1368-BCZ) activated both ER and AhR pathways, and upregulated the expression of ER pathway target gene trefoil factor 1 (tff1) and AhR pathway target genes cytochrome P450 1A1 (cyp1a1) and cytochrome P450 1B1 (cyp1b1). The activation of the ER pathway induced by 1368-BCZ was partly dependent on the presence of AhR, while the upregulation of the AhR pathway target genes was further enhanced with the addition of ER blocker. Therefore, 1368-BCZ can activate both the ER and AhR pathways and cause interactions between them. This study supplemented the understanding of the action mechanisms of BCZs in ER-positive breast cancer cells.
-
-
Parette R, McCrindle R, McMahon K S, et al. Halogenated indigo dyes:A likely source of 1,3,6,8-tetrabromocarbazole and some other halogenated carbazoles in the environment[J]. Chemosphere, 2015, 127:18-26 Karon K, Lapkowski M, Juozas G. Electrochemical and UV-Vis/ESR spectroelectrochemical properties of polymers obtained from isomeric 2,7- and 3,6- linked carbazole trimers; influence of the linking topology on polymers properties[J]. Electrochimica Acta, 2014, 123:176-182 Amine-Khodja A, Boulkamh A, Boule P. Photochemical behaviour of phenylurea herbicides[J]. Photochemical & Photobiological Sciences, 2004, 3(2):145-156 Mumbo J, Lenoir D, Henkelmann B, et al. Enzymatic synthesis of bromo- and chlorocarbazoles and elucidation of their structures by molecular modeling[J]. Environmental Science and Pollution Research International, 2013, 20(12):8996-9005 Guo J H, Li Z N, Ranasinghe P, et al. Spatial and temporal trends of polyhalogenated carbazoles in sediments of upper great lakes:Insights into their origin[J]. Environmental Science & Technology, 2017, 51(1):89-97 Mumbo J, Pandelova M, Mertes F, et al. The fingerprints of dioxin-like bromocarbazoles and chlorocarbazoles in selected forest soils in Germany[J]. Chemosphere, 2016, 162:64-72 Wu Y, Qiu Y L, Tan H L, et al. Polyhalogenated carbazoles in sediments from Lake Tai (China):Distribution, congener composition, and toxic equivalent evaluation[J]. Environmental Pollution, 2017, 220(Pt A):142-149 Mumbo J, Henkelmann B, Abdelaziz A, et al. Persistence and dioxin-like toxicity of carbazole and chlorocarbazoles in soil[J]. Environmental Science and Pollution Research International, 2015, 22(2):1344-1356 Kaehler S, Williams G A. Distribution of algae on tropical rocky Shores:Spatial and temporal patterns of non-coralline encrusting algae in Hong Kong[J]. Marine Biology, 1996, 125(1):177-187 Lee S C, Williams G A, Brown G D. Maculalactone L and three halogenated carbazole alkaloids from Kyrtuthrix maculans[J]. Phytochemistry, 1999, 52(3):537-540 Wu Y, Tan H L, Sutton R, et al. From sediment to top predators:Broad exposure of polyhalogenated carbazoles in San Francisco Bay (U.S.A.)[J]. Environmental Science & Technology, 2017, 51(4):2038-2046 Wu Y, Tan H L, Zhou C L, et al. Bioaccumulation and spatiotemporal trends of polyhalogenated carbazoles in Great Lakes fish from 2004 to 2016[J]. Environmental Science & Technology, 2018, 52(8):4536-4545 周音巧. 土壤中的1,3,6,8-四溴咔唑在蚯蚓体内的积累及生态毒性[D]. 杭州:浙江工业大学, 2019:37-38 Zhou Y Q. Accumulation and ecotoxicities of 1,3 ,6,8-tetrabromocarbazole in earthworms(Eisenia foetida) from spiked artificial soils[D]. Hangzhou:Zhejiang University of Technology, 2019:37-38(in Chinese)
Ji C Y, Yan L, Chen Y C, et al. Evaluation of the developmental toxicity of 2,7-dibromocarbazole to zebrafish based on transcriptomics assay[J]. Journal of Hazardous Materials, 2019, 368:514-522 Fang M L, Guo J H, Chen D, et al. Halogenated carbazoles induce cardiotoxicity in developing zebrafish (Danio rerio) embryos[J]. Environmental Toxicology and Chemistry, 2016, 35(10):2523-2529 Zhang J W, Zhang C, Du Z K, et al. Emerging contaminant 1,3,6,8-tetrabromocarbazole induces oxidative damage and apoptosis during the embryonic development of zebrafish (Danio rerio)[J]. Science of the Total Environment, 2020, 743:140753 Ma D, Xie H Q, Zhang W L, et al. Aryl hydrocarbon receptor activity of polyhalogenated carbazoles and the molecular mechanism[J]. The Science of the Total Environment, 2019, 687:516-526 Riddell N, Jin U H, Safe S, et al. Characterization and biological potency of mono-to tetra-halogenated carbazoles[J]. Environmental Science & Technology, 2015, 49(17):10658-10666 Yue S Q, Zhang T, Shen Q Q, et al. Assessment of endocrine-disrupting effects of emerging polyhalogenated carbazoles (PHCZs):In vitro, in silico, and in vivo evidence[J]. Environment International, 2020, 140:105729 Hsieh C C, Lambe M, Trichopoulos D, et al. Early life exposure to oestrogen and testicular cancer risk:Evidence against an aetiological hypothesis[J]. British Journal of Cancer, 2002, 86(8):1363-1364 Salisbury T B, Morris G Z, Tomblin J K, et al. Aryl hydrocarbon receptor ligands inhibit igf-ii and adipokine stimulated breast cancer cell proliferation[J]. ISRN Endocrinology, 2013, 2013:104850 Trombino A F, Near R I, Matulka R A, et al. Expression of the aryl hydrocarbon receptor/transcription factor (AhR) and AhR-regulated CYP1 gene transcripts in a rat model of mammary tumorigenesis[J]. Breast Cancer Research and Treatment, 2000, 63(2):117-131 谢昕岑, 于淼, 汝少国. 基于AhR信号通路的抗雌激素效应及其机制研究进展[J]. 生态毒理学报, 2021, 16(5):148-159 Xie X C, Yu M, Ru S G. Research advances of anti-estrogenic effect based on AhR signaling pathway and its mechanism[J]. Asian Journal of Ecotoxicology, 2021, 16(5):148-159(in Chinese)
Ahmed S, Valen E, Sandelin A, et al. Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters[J]. Toxicological Sciences, 2009, 111(2):254-266 Shanle E K, Xu W. Endocrine disrupting chemicals targeting estrogen receptor signaling:Identification and mechanisms of action[J]. Chemical Research in Toxicology, 2011, 24(1):6-19 Safe S, Wormke M. Inhibitory aryl hydrocarbon receptor-estrogen receptor alpha cross-talk and mechanisms of action[J]. Chemical Research in Toxicology, 2003, 16(7):807-816 Beischlag T V, Luis Morales J, Hollingshead B D, et al. The aryl hydrocarbon receptor complex and the control of gene expression[J]. Critical Reviews in Eukaryotic Gene Expression, 2008, 18(3):207-250 张婉君, 范瑞祺, 黄超, 等. 有害结局路径在农药风险评估及管理中应用的探讨[J]. 生态毒理学报, 2021, 16(6):60-69 Zhang W J, Fan R Q, Huang C, et al. Discussion on application of adverse outcome pathway in pesticides risk assessment and management[J]. Asian Journal of Ecotoxicology, 2021, 16(6):60-69(in Chinese)
李子璇, 杨雪葳, 任利翔, 等. 有机氯农药介导的内分泌干扰相关不良结局通路(AOP)的研究进展[J]. 农药, 2021, 60(10):703-711 Li Z X, Yang X W, Ren L X, et al. Advances in studies on endocrine disruption-related adverse outcome pathways (AOP) mediated by organochlorine pesticides[J]. Agrochemicals, 2021, 60(10):703-711(in Chinese)
Xu T, Hu X X, Yang G L, et al. HIF-1alpha/VEGF pathway mediates 1,3,6,8-tetrabromo-9 H-carbazole-induced angiogenesis:A potential vascular toxicity of an emerging contaminant[J]. Journal of Hazardous Materials, 2022, 432:128718 Prest S J, May F E B, Westley B R. The estrogen-regulated protein, TFF1, stimulates migration of human breast cancer cells[J]. FASEB Journal:Official Publication of the Federation of American Societies for Experimental Biology, 2002, 16(6):592-594 Pelden S, Insawang T, Thuwajit C, et al. The trefoil factor 1(TFF1) protein involved in doxorubicin-induced apoptosis resistance is upregulated by estrogen in breast cancer cells[J]. Oncology Reports, 2013, 30(3):1518-1526 Do M T, Kim H G, Tran T T, et al. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression[J]. Toxicology and Applied Pharmacology, 2014, 280(1):138-148 Kerzee J K, Ramos K S. Constitutive and inducible expression of cyp1a1 and cyp1b1 in vascular smooth muscle cells[J]. Circulation Research, 2001, 89(7):573-582 Hindiyeh M Y, Moran-Gilad J, Manor Y, et al. Development and validation of a real time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay for investigation of wild poliovirus type 1-South Asian (SOAS) strain reintroduced into Israel, 2013 to 2014[J]. Euro Surveillance, 2014, 19(7):20710 Liu H, Wormke M, Safe S H, et al. Indolo[3, 2-b] carbazole:A dietary-derived factor that exhibits both antiestrogenic and estrogenic activity[J]. Journal of the National Cancer Institute, 1994, 86(23):1758-1765 Liu S X, Abdelrahim M, Khan S, et al. Aryl hydrocarbon receptor agonists directly activate estrogen receptor alpha in MCF-7 breast cancer cells[J]. Biological Chemistry, 2006, 387(9):1209-1213 Gong P, Madak-Erdogan Z, Flaws J A, et al. Estrogen receptor-α and aryl hydrocarbon receptor involvement in the actions of botanical estrogens in target cells[J]. Molecular and Cellular Endocrinology, 2016, 437:190-200 孙佳琦, 张甘霖, 于明薇, 等. 植物雌激素与乳腺癌发病发展的研究进展[J]. 现代生物医学进展, 2016, 16(12):2368-2371 Sun J Q, Zhang G L, Yu M W, et al. Research progress of phytoestrogen in incidence and development of breast cancer[J]. Progress in Modern Biomedicine, 2016, 16(12):2368-2371(in Chinese)
Sadikovic B, Rodenhiser D I. Benzopyrene exposure disrupts DNA methylation and growth dynamics in breast cancer cells[J]. Toxicology and Applied Pharmacology, 2006, 216(3):458-468 Brunnberg S, Pettersson K, Rydin E, et al. The basic helix-loop-helix-PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription[J]. Proceedings of the National Academy of Sciences of the United States of America, 2003, 100(11):6517-6522 Abdelrahim M, Smith R 3rd, Safe S. Aryl hydrocarbon receptor gene silencing with small inhibitory RNA differentially modulates Ah-responsiveness in MCF-7 and HepG2 cancer cells[J]. Molecular Pharmacology, 2003, 63(6):1373-1381 Yip C H, Rhodes A. Estrogen and progesterone receptors in breast cancer[J]. Future Oncology, 2014, 10(14):2293-2301 Saito R, Miki Y, Hata S, et al. Aryl hydrocarbon receptor induced intratumoral aromatase in breast cancer[J]. Breast Cancer Research and Treatment, 2017, 161(3):399-407 -
点击查看大图
计量
- 文章访问数: 2278
- HTML全文浏览数: 2278
- PDF下载数: 122
- 施引文献: 0
下载:
